PASLI disease

PASLI stands for “p110 delta activating mutation causing senescent T cells, lymphadenopathy, and immunodeficiency.” The immunodeficiency manifests as recurrent infections usually starting in childhood.

These include bacterial infections of the respiratory system and chronic viremia due to Epstein–Barr virus (EBV) and/or cytomegalovirus (CMV).

Investigators Carrie Lucas, Michael Lenardo, and Gulbu Uzel at the National Institute of Allergy and Infectious Diseases at the U.S. National Institutes of Health and Sergey Nejentsev at the University of Cambridge, UK simultaneously described a mutation causing this condition, which they called activated PI3K delta syndrome (APDS).

[1][2] Clinically, PASLI disease is characterized by recurrent sinopulmonary infections that can lead to progressive airway damage.

People also have lymphoproliferation (large lymph nodes and spleen), chronic viremia due to EBV or CMV, distinctive lymphoid nodules at mucosal surfaces, autoimmune cytopenias, and EBV-driven B cell lymphoma.

This “variable expressivity,” even within the same family, can be striking and may be explained by differences in lifestyle, exposure to pathogens, treatment efficacy, or other genetic modifiers.

A variant of PASLI disease can all be caused by heterozygous splice site mutation in PIK3R1, which encodes the p85α, p55α, and p50α regulatory PI3K subunits.

This effectively reduced hepatosplenomegaly and lymphadenopathy, most likely by restoring the normal balance of naïve, effector, and memory cells in the patients' immune system.

Figure 2: Proposed model for the effects of activating substitutions (red asterisk) in p110δ [ 1 ]
Figure 1: p110δ protein domains; vertical red lines indicate positions of substitution mutations. ABD, adaptor-binding domain; RDB, Ras-binding domain. [ 1 ]